CN116751195A - 联吡啶类化合物、其可药用的盐以及制备方法和应用 - Google Patents
联吡啶类化合物、其可药用的盐以及制备方法和应用 Download PDFInfo
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- CN116751195A CN116751195A CN202310742655.5A CN202310742655A CN116751195A CN 116751195 A CN116751195 A CN 116751195A CN 202310742655 A CN202310742655 A CN 202310742655A CN 116751195 A CN116751195 A CN 116751195A
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- Prior art keywords
- cancer
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- bipyridine
- alkyl
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Abstract
本发明公开了一类联吡啶类化合物或其可药用的盐，以及制备方法和在医药上的应用。本发明还公开了该类型具体46个化合物及其化学合成方法，合成路线简单，易于操作和实施，并且所需试剂易于购买。同时测试了46个化合物对9种肿瘤细胞的增殖抑制活性，结果显示相比于此类天然产物的增殖抑制活性的30μM(IC50)，化合物的增殖抑制活性有了极大的提高，经过结构修饰之后活性可以达到几十至几百纳摩尔。另外，多个化合物的对多种癌细胞的增殖活性优于阿霉素的作用效果，与5‑氟尿嘧啶结果相当，可以作为多种癌症相关疾病的治疗药物，也可作为蛋白抑制剂用于治疗相关疾病或病症的用途。
Description
技术领域
本发明涉及医药技术领域，具体涉及一类联吡啶类化合物、其可药用的盐以及制备方法和应用。
背景技术
癌症是影响人类生命健康与生命质量的第一大原因，也是世界性的难题。临床治疗手段主要包括局部治疗如手术切除、放射治疗和化学疗法等疗法。目前化疗药物有紫杉醇、含铂药物、5-氟尿嘧啶等。然而，广谱抗肿瘤药物也存在一些不良反应，如骨髓毒性、消化道反应、肝毒性等难以控制。
联吡啶衍生物是一类具有独特二联吡啶骨架的生物碱，从蓝色链霉菌(Streptomyces caeruleus)中发现并分离出第一个联吡啶类化合物——浅蓝霉素Careulomycin A(Funk,A.；Divekar,P.V.Caerulomycin,a new antibiotic fromStreptomyces caeruleus Baldacci.I.Production,isolation,assay,and biologicalproperties[J].Can.J.Microbiol.1959,5,317-321.)，随后又陆续发现了多个衍生物Careulomycin B-N及类似物。该类型化合物通常具有独特的2,2′-联吡啶骨架，最初研究发现它们有很强的抗菌及免疫抑制活性。其中发明人分离得到四个联吡啶结构的天然产物如下式1-4所示，有研究发现联吡啶类化合物对肿瘤细胞HL-60、K562、KB和A549的增值均有抑制作用，其中化合物a对HL-60和A549肿瘤细胞的增殖抑制活性分别为1.6μM(IC50)和8.4μM(IC50)，化合物b对肿瘤细胞HL-60、K562、KB和A549的增值均有抑制活性，分别为大于50μM(IC50)、1.8μM(IC50)、大于50μM(IC50)和3.1μM(IC50)，化合物c与化合物d对HL-60、K562、KB和A549四种肿瘤细胞的增殖抑制活性均大于50μM(IC50)(dx.doi.org/10.1021/np200258h，J.Nat.Prod.2011,74,1751–1756)。此外，发明人自行测试了化合物a-d对肿瘤细胞HCT-116和MDA-MB-231的增殖抑制活性均大于30μM(IC50)。
前期我们从西太平洋深海来源的放线菌Streptomyces sp.BC6次级代谢产物中分离得到多个联吡啶天然产物，经测试发现化合物对多种癌细胞的增殖有一定的抑制作用，但活性有待提高。此次我们通过化学合成得到了一系列联吡啶衍生物，用于治疗癌症相关疾病或病症的用途。
发明内容
本发明提供了一类联吡啶类化合物或其可药用的盐，此类化合物对多种癌细胞具有抑制细胞增殖作用。本发明亦提供药物组合物及药物，其包括单独的或并与额外抗癌治疗剂或缓解剂组合的本发明的化合物或盐。
联吡啶类化合物或其可药用的盐，所述联吡啶类化合物具有如下式I所示结构：
式I中：
X1、X2、X3分别独立为C原子或N原子且X1、X2、X3中有且仅有一个为N原子，Y1、Y2不相同且分别独立为C原子或N原子，L为酰胺键、酯键或N原子；
Ra、Rb分别独立为氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基或杂环基；
R1为烷基、烷氧基、环烷基或杂环基，其中烷基、烷氧基、杂环基可任选地被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、杂环基中的一个或多个取代基所取代。
进一步的，联吡啶类化合物或其可药用的盐，所述联吡啶类化合物具有如下式II～XIV任一所示结构：
式II～XIV中，X1、X2、X3分别独立为C原子或N原子且X1、X2、X3中有且仅有一个为N原子，R2为H、羟基或烷氧基，R3为H或烷基；
式II、V、VIII、X、XII中，R4、R5分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基，或者，R4、R5连接成环；
式III中，R4、R5分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式IV、IX中，R5为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式VI、VII、XI中，R4-R8分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式XIII中，R4-R6分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式XIV中，R4-R10分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基。
更进一步的，所述联吡啶类化合物为以下任一化合物：
本发明还提供了所述的联吡啶类化合物的制备方法，所述联吡啶类化合物具有如式II～VII任一所示结构，所述制备方法为采用相应原料通过碱性条件下的酰胺化反应缩合形成酰胺键从而得到如式II～VII任一所示结构的联吡啶类化合物。
本发明还提供了所述的联吡啶类化合物的制备方法，所述联吡啶类化合物具有如式VIII～XIV任一所示结构，所述制备方法为采用相应原料通过连吡啶环上的卤素原子与伯胺或叔胺在碱性条件、催化剂存在的情况下微波或加热进行偶联反应，从而得到如式VIII～XIV任一所示结构的联吡啶类化合物。
以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选为N,N-二异丙基乙胺和/或三乙胺。
以上合成方案中所述的缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯(HBTU)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷；优选为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)。
以上合成方案中，反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
本发明还提供了一种药物组合物，所述药物组合物含有所述的联吡啶类化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂和/或赋形剂。
本发明涉及本发明化合物或其医药学上可接受的盐，其用作药物，尤其是用于治疗癌症的药物。
本发明涉及本发明化合物或其医药学上可接受的盐，其用于治疗个体中异常的细胞生长，尤其是癌症。
本发明提供任一本文所述通式的化合物或其医药学上可接受的盐用于制备用以治疗个体中异常的细胞生长的药剂的用途。
在前述化合物、方法及用途的常见实施方案中，所述异常的细胞生长是癌症。
本发明还提供了所述的联吡啶类化合物或其可药用的盐，或者，所述的药物组合物在制备用于治疗和/或预防疾病的药物中的应用。所述疾病优选为癌症。所述癌症优选为乳腺癌、子宫内膜癌、卵巢癌、阴道癌、输卵管癌、宫颈癌、肾癌、膀胱癌、尿路上皮癌、尿道癌、前列腺癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、鼻咽癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、神经纤维瘤、神经胶质瘤、神经母细胞瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌和胃肠道间质瘤。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
方案一，中间体的反应通式：
第一步
间氯过氧苯甲酸(8.1g，32.86mmol)溶于二氯甲烷(6.5mL)中，充分搅拌溶解。在冰水浴条件下，将间氯过氧苯甲酸溶液缓慢添加到联吡啶a(5.0g，32.1mmol)的二氯甲烷(25mL)溶液中，室温下反应2h。反应完成后：反应混合物用二氯甲烷稀释至最终体积为150mL，并用饱和的硫代硫酸钠(2×20mL)和20％氢氧化钠水溶液(2×20mL)洗涤，收集有机相，用无水硫酸钠干燥，过滤，并减压浓缩。将所得粗产物过柱，己烷/石油醚(6：1，250mL)，得到2-吡啶-2-基吡啶-1-氧化物b，4.7g，产率94％。
第二步
冰浴条件下，在1L烧瓶中，加入浓硫酸(0.04vol，8mL)，剧烈搅拌下将2,2'-联吡啶N-氧化物b(1.883g，11mmol)缓慢加入到浓硫酸中(添加时间，15分钟，放热反应)，保持反应体系温度低于80℃(溶液呈深棕色)，搅拌10分钟，然后通过加料漏斗缓慢添加浓硝酸(0.02vol，4mL)(添加时间，12分钟内)，观察到从棕色到橙色的颜色变化，将所得反应体系加热到105℃，反应时间4.5h，在此期间大量的NO2气体放出(安装了一个氢氧化钠水溶液的捕集阱以中和这些气体)。反应完成后：反应混合物冷却至室温，倒入三角瓶。然后，用36％氢氧化钠水溶液中和至pH 4.0，观察到所需产物的沉淀，在中和后立即过滤。产物用水洗涤并真空干燥，得到所需产物，黄色固体，1.56g，产率83％。
第三步
在冰水浴条件下，甲醇钠(0.03equiv，1.250g，2.31mmol)缓慢加入到适量的无水甲醇中(注意：轻微放热反应)，向反应体系中缓慢加入化合物c(1.676g，7.7mmol)，将反应体系加热至68℃，回流，1h。反应完成后：反应体系冷却到室温，减压浓缩除去溶剂。用二氯甲烷萃取。无水硫酸钠干燥有机相，过滤，并在减压下浓缩至干燥，得到黄色固体d，1.35g，产率81％。
第四步
化合物d(1.35g,6.7mmol)溶解在适量的乙腈中，室温充分搅拌，加入三乙胺(1.2mL,0.80mol)和氰基磷酸二乙酯(3mL,0.2mmol)，将反应混合物加热至82℃，反应时间30min。反应完成后：将反应液倒入2L锥形瓶中，冷却后形成沉淀。过滤，用乙腈洗涤，减压干燥得到产品，白色固体e，0.986g，产率73％。
第五步
将化合物e(1.175g,5.5mmol)溶于10ml乙醇中，搅拌，向反应溶液中缓慢加入氢氧化钠溶液(14.8mM,15mL)中，存在一定的放热现象，反应混合物加热至82℃，反应1.5h。反应完成后：将反应溶液冷却至10℃，倒入2L锥形烧瓶，直接过滤，用乙醇和水清洗得到的固体，在真空干燥箱中烘干，得到钠盐呈白色固体。后按照1：1摩尔量的加入盐酸，得到化合物白色固体f，质量1.06g，产率90.2％。
第六步
反应底物f(130.0mg，0.93mmol)溶于10ml的N,N-二甲基甲酰胺，向反应体系中加入三乙胺(336.0mg,3.3mmol)，按照摩尔比1：1.2加入底物R1以及1-羟基苯并三唑(135.0mg,0.998mmol)和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(191.0mg,0.998mmol)。室温搅拌反应18h。反应完成后：减压旋蒸(50℃)除去N,N-二甲基甲酰胺，向其中加入10ml水，使用乙酸乙酯萃取(3X10mL)。无水硫酸钠干燥，减压旋蒸，过柱，纯化得到各实例化合物，产率29％-56％。
4-甲氧基-N-(噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：48％。1H NMR(600MHz,METHANOL-D4)δ8.82–8.77(m,1H),8.75(d,J＝8.1Hz,1H),8.28(td,J＝7.8,1.7Hz,1H),8.15(d,J＝2.4Hz,1H),7.88(d,J＝2.4Hz,1H),7.73(ddd,J＝7.6,5.1,1.2Hz,1H),7.55(d,J＝3.5Hz,1H),7.24(d,J＝3.6Hz,1H),4.06(s,4H).13C NMR(151MHz,METHANOL-D4)δ170.34,151.17,148.10,142.39,142.35,138.70,127.04,124.20,115.43,111.86,111.18,56.91.HRESIMS m/z313.0756[M+H]+(calcd for C15H12N4O2S 313.0759).
4-甲氧基-N-(5-甲基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
淡黄色固体，产率：56％。1H NMR(600MHz,DMSO-d6)δ12.36(s,1H),9.04(dd,J＝8.0,1.1Hz,1H),8.76(dt,J＝4.7,1.4Hz,1H),8.17(d,J＝2.5Hz,1H),8.14–8.09(m,1H),7.74(d,J＝2.4Hz,1H),7.65–7.57(m,1H),7.29(d,J＝1.3Hz,1H),4.02(s,3H),2.41(d,J＝1.3Hz,3H).13C NMR(151MHz,DMSO-D6)δ168.26,162.68,158.78,156.35,153.58,150.44,148.89,139.04,135.76,128.00,125.81,123.16,110.20,109.92,56.64,11.68.HRESIMSm/z 327.0915[M+H]+(calcd for C16H14N4O2S 327.0916).
2-(4-甲氧基-[2,2'-联吡啶]-6-甲酰胺基)噻唑-4-甲酰胺
白色固体，产率：36％。1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.07(dt,J＝7.9,1.2Hz,1H),8.80–8.76(m,1H),8.20(dd,J＝2.5,1.1Hz,1H),8.17–8.06(m,1H),7.96(s,1H),7.78(dd,J＝2.5,1.2Hz,1H),7.64(s,1H),7.63–7.58(m,1H),7.46(s,1H),4.04(s,2H).13C NMR(151MHz,DMSO-D6)δ167.73,163.04,162.46,157.42,153.64,153.17,149.51,148.61,145.30,138.06,125.24,122.53,118.66,109.85,109.50,56.13.HRESIMS m/z356.0816[M+H]+(calcd for C16H14N5O3S 356.0817).
2-(4-甲氧基-[2,2'-联吡啶]-6-甲酰胺基)噻唑-4-甲酸乙酯
白色固体，产率：43％。1H NMR(600MHz,DMSO-d6)δ13.06(s,1H),9.17(dt,J＝8.0,1.1Hz,1H),8.78(d,J＝4.5Hz,1H),8.21(s,1H),8.21(d,J＝2.5Hz,1H),8.13(t,J＝7.6Hz,1H),7.78(d,J＝2.5Hz,1H),7.61(t,J＝6.2Hz,1H),4.33(q,J＝7.1Hz,2H),4.04(s,3H),1.33(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-D6)δ168.20,164.02,161.57,158.67,150.16,141.92,133.83,128.27,125.79,124.26,123.35,112.78,112.17,110.54,110.04,61.23,56.65,14.78.HRESIMS m/z 385.0968[M+H]+(calcd for C18H17N4O4S385.0971).
N-(5-氰噻唑-2-基)-4-甲氧基-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：32％。1H NMR(600MHz,DMSO-d6)δ13.49(s,1H),9.11(dt,J＝7.9,1.2Hz,1H),8.74–8.67(m,1H),8.51(s,1H),8.17(d,J＝2.5Hz,1H),8.01(td,J＝7.7,1.8Hz,1H),7.74(d,J＝2.5Hz,1H),7.51(ddd,J＝7.4,4.7,1.2Hz,1H),4.00(s,3H).13CNMR(151MHz,DMSO-D6)δ167.59,164.02,162.22,150.25,148.98,128.81,128.62,128.01,126.38,125.10,122.58,113.31,110.27,109.52,98.50,56.10.HRESIMS m/z338.0708[M+H]+(calcd for C15H12N4O2S 338.0712).
N-(4-甲氧基-2-基)-4-甲氧基-[2,2'-联吡啶]-6-甲酰胺
淡黄色固体，产率：29％。1H NMR(600MHz,DMSO-d6)δ13.15(s,1H),9.16(dt,J＝8.0,1.1Hz,1H),8.75(dd,J＝4.9,1.8Hz,1H),8.52(s,1H),8.21(d,J＝2.5Hz,1H),8.08(td,J＝7.8,1.8Hz,1H),7.77(d,J＝2.5Hz,1H),7.58(dd,J＝7.6,4.8Hz,1H),4.03(s,3H).13C NMR(151MHz,NONE)δ167.61,163.56,159.31,153.31,149.17,148.66,137.85,128.00,125.15,122.64,120.58,114.86,110.07,109.42,56.08.HRESIMS m/z 338.0706[M+H]+(calcd for C15H12N4O2S 338.0712).
方案二，中间体的反应通式：
第一步
间氯过氧苯甲酸(mCPBA 8.1g，32.86mmol)溶于二氯甲烷(6.5mL)中，充分搅拌溶解。在冰水浴条件下，将间氯过氧苯甲酸的溶液缓慢添加到溶解有联吡啶1(5.0g，32.1mmol)的二氯甲烷(25mL)溶液中，室温下反应2h。反应完成后：将反应混合物用二氯甲烷稀释至终体积为150mL，并用饱和的硫代硫酸钠溶液(2×20mL)和20％氢氧化钠溶液(2×20mL)洗涤，收集有机相，有机相用无水硫酸钠干燥，过滤，并减压浓缩。将所得粗产物过柱，己烷/石油醚(6：1，250mL)，得到化合物2。
第二步
化合物2(1.35g,6.7mmol)溶解在适量的乙腈中，室温充分搅拌，加入三乙胺(1.2mL,0.80mol)和氰基磷酸二乙酯(3mL,0.2mmol)，将反应混合物加热至82℃，缓慢溶解，反应30min。反应完成后：将反应液倒入2L锥形瓶中，冷却后形成沉淀。过滤，用乙腈洗涤，减压干燥得到产品的白色固体3。
第三步
将化合物3(1.175g,5.5mmol)溶于10ml乙醇中，搅拌，向反应溶液中缓慢加入氢氧化钠溶液(14.8mM,15mL)中，存在一定的放热现象，反应混合物加热至82℃，反应1.5h。反应完成后：将反应溶液冷却至10℃，倒入2L锥形烧瓶，直接过滤，用乙醇和水清洗得到的固体，在真空干燥箱中烘干，得到钠盐呈白色固体。后按照1：1摩尔量的加入盐酸，得到化合物4。
第四步
反应底物4(130.0mg，0.93mmol)溶于10ml的N,N-二甲基甲酰胺，向反应体系中加入三乙胺(336.0mg,3.3mmol)，反应体系中按照摩尔比1：1.2加入底物R1以及1-羟基苯并三唑(135.0mg,0.998mmol)和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(191.0mg,0.998mmol)。室温反应18h。反应完成后：减压旋蒸(50℃)除去N,N-二甲基甲酰胺，向其中加入10ml水，使用乙酸乙酯萃取。有机相用水洗，无水硫酸钠干燥，旋干，过柱，纯化得到各实例化合物，产率17％-83％。
N-(噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：53％。1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),9.04(dt,J＝8.1,1.1Hz,1H),8.81(d,J＝5.0Hz,1H),8.67(ddd,J＝6.6,2.3,0.9Hz,1H),8.28–8.22(m,2H),8.21(s,1H),7.66(d,J＝8.8Hz,1H),7.61(d,J＝3.5Hz,1H),7.36(d,J＝3.5Hz,1H).13C NMR(151MHz,DMSO-D6)δ162.49,158.33,158.08,157.75,148.00,147.63,139.60,137.95,125.50,124.51,123.90,122.83,116.32,114.56.HRESIMS m/z 283.0650[M+H]+(calcdfor C14H10N4OS 283.0654).
N-((噻唑-5基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：45％。1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),8.98(dt,J＝7.9,1.2Hz,1H),8.78(ddd,J＝4.9,1.8,0.8Hz,1H),8.74(s,1H),8.68(dd,J＝6.7,2.3Hz,1H),8.29–8.21(m,2H),8.13(td,J＝7.7,1.7Hz,1H),8.11(d,J＝0.9Hz,1H),7.59(ddd,J＝7.5,4.8,1.2Hz,1H).13C NMR(151MHz,DMSO-D6)δ162.11,154.90,154.17,149.51,148.85,147.45,139.93,138.54,135.68,130.85,125.59,124.45,123.90,122.63.HRESIMS m/z283.0653[M+H]+(calcd for C14H10N4OS 283.0654).
N-(5-甲基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
淡黄色固体，产率：52％。1H NMR(600MHz,DMSO-d6)δ12.42(s,1H),9.03(dt,J＝8.0,1.1Hz,1H),8.80–8.73(m,1H),8.70–8.60(m,1H),8.29–8.19(m,2H),8.12(t,J＝7.7Hz,1H),7.60(t,J＝6.4Hz,1H),7.29(s,0H),7.26(q,J＝1.2Hz,1H),2.38(d,J＝1.3Hz,3H).13C NMR(151MHz,DMSO-D6)δ162.88,158.84,158.60,156.44,148.81,148.63,140.02,135.73,127.95,125.80,124.83,124.19,123.14,115.22,11.68.HRESIMS m/z 297.0804[M+H]+(calcd for C15H12N4OS 297.0810).
N-(4-(三氟甲基)噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：18％。1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),9.15(dt,J＝7.9,1.2Hz,1H),8.76–8.72(m,1H),8.67(dd,J＝7.4,1.6Hz,1H),8.26–8.19(m,2H),8.10–8.05(m,2H),7.56(t,J＝6.1Hz,1H).13C NMR(151MHz,DMSO-D6)δ164.34,160.65,158.78,158.54,149.15,148.11,139.95,138.63,138.38,125.66,125.03,124.42,123.21,118.02,118.01.HRESIMS m/z 351.0524[M+H]+(calcd for C15H9F3N4OS 351.0527).
N-(4-甲基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：49％。1H NMR(600MHz,DMSO-d6)δ12.56(s,1H),9.07(dt,J＝8.0,1.1Hz,1H),8.76(d,J＝5.1Hz,1H),8.68–8.62(m,1H),8.25–8.18(m,2H),8.11(t,J＝7.8Hz,1H),7.59(t,J＝6.3Hz,1H),6.89(p,J＝1.1Hz,1H),2.32(d,J＝1.1Hz,3H).13C NMR(151MHz,DMSO-D6)δ163.12,158.81,158.57,157.62,148.87,148.60,147.67,140.01,139.37,125.76,124.82,124.15,123.17,109.37,17.41.HRESIMS m/z 297.0808[M+H]+(calcd for C15H12N4OS 297.0810).
N-(4-(羟甲基)噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：59％。1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),9.07(dt,J＝8.0,1.1Hz,1H),8.77–8.74(m,1H),8.65(dd,J＝6.1,2.9Hz,1H),8.23–8.19(m,2H),8.14–8.04(m,1H),7.58(t,J＝6.1Hz,1H),7.05(t,J＝1.2Hz,1H),4.52(d,J＝1.2Hz,2H).13C NMR(151MHz,DMSO-D6)δ162.71,158.26,157.45,152.82,148.45,148.03,139.45,125.16,124.26,123.59,122.57,116.78,114.89,108.92,59.91.HRESIMS m/z313.0756[M+H]+(calcd for C15H13N4O2S 313.0759).
N-(4-甲酸乙酯基噻唑-2-基)[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：47％。1H NMR(600MHz,DMSO-d6)δ13.11(s,1H),9.16(dt,J＝8.0,1.1Hz,1H),8.80(d,J＝4.8Hz,1H),8.70(dd,J＝7.2,1.8Hz,1H),8.30–8.22(m,2H),8.20(s,1H),8.18–8.15(m,1H),7.63(s,1H),4.32(q,J＝7.1Hz,2H),1.32(t,J＝7.1Hz,3H).13CNMR(151MHz,CHLOROFORM-D)δ163.55,161.44,160.96,158.19,158.11,157.94,147.74,141.30,139.38,128.91,125.17,124.41,123.84,123.60,122.69,60.61,14.16.HRESIMSm/z 355.0869[M+H]+(calcd for C17H14N4O3S 355.0865).
2-([2,2'-联吡啶]-6-甲酰氨基)噻唑-5-甲酸乙酯
白色固体，产率：37％。1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),9.08(dt,J＝8.0,1.1Hz,1H),8.73(dt,J＝4.8,1.5Hz,1H),8.67(dd,J＝7.2,1.8Hz,1H),8.27(s,1H),8.25–8.19(m,2H),8.10–8.04(m,1H),7.56–7.50(m,1H),4.27(dq,J＝12.4,7.1Hz,2H),1.28(dt,J＝9.0,7.1Hz,3H).13C NMR(151MHz,DMSO-D6)δ164.21,162.73,161.96,149.20,148.07,145.76,139.99,133.58,129.22,128.90,125.67,125.09,124.49,123.09,122.67,61.54,14.73.HRESIMS m/z 355.0861[M+H]+(calcd for C17H14N4O3S355.0865).
2-([2,2'-联吡啶]-6-甲酰胺基)噻唑-4-甲酰胺
黄色固体，产率：33％。1H NMR(600MHz,DMSO-d6)δ12.68(s,1H),9.08(dt,J＝8.0,1.1Hz,1H),8.77(dt,J＝4.8,1.5Hz,1H),8.68(dd,J＝7.1,1.9Hz,1H),8.28–8.23(m,2H),8.15–8.06(m,1H),7.94(s,1H),7.66–7.61(m,1H),7.60–7.56(m,1H),7.45(s,1H).13C NMR(151MHz,CHLOROFORM-D)δ168.57,167.76,162.80,158.86,154.15,154.10,152.99,150.59,144.75,144.67,130.38,129.73,128.91,127.68,123.89.HRESIMS m/z 326.0709[M+H]+(calcd for C15H11N5O2S 326.0712).
2-([2,2'-联吡啶]-6-甲酰胺)-N,N-二甲基噻唑-4-甲酰胺
黄色固体，产率：19％。1H NMR(600MHz,DMSO-d6)δ12.85(s,1H),12.54(s,1H),9.08(dt,J＝7.9,1.2Hz,1H),8.73–8.69(m,1H),8.66(dd,J＝7.4,1.6Hz,1H),8.43(d,J＝0.8Hz,1H),8.26–8.18(m,2H),8.04(td,J＝7.7,1.8Hz,1H),7.52(ddd,J＝7.6,4.8,1.1Hz,1H),2.97(s,3H),2.92(s,3H).HRESIMS m/z 354.1020[M+H]+(calcd for C17H15N5O2S354.1025).
N-(4-氰基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：27％。1H NMR(600MHz,DMSO-d6)δ13.21(s,1H),9.17(dt,J＝8.0,1.1Hz,1H),8.79(dd,J＝5.0,1.6Hz,1H),8.72(dd,J＝7.0,2.1Hz,1H),8.52(d,J＝0.8Hz,1H),8.32–8.24(m,2H),8.14(t,J＝7.9Hz,1H),7.62(t,J＝6.2Hz,1H).13CNMR(151MHz,DMSO-D6)δ164.25,159.95,158.62,153.70,149.02,147.95,140.05,139.01,128.55,125.77,125.17,124.52,123.22,121.14,115.43.HRESIMS m/z 307.0604[M+H]+(calcdfor C15H9N5OS 307.0606).
N-(5-氰基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：23％。1H NMR(600MHz,DMSO-d6)δ13.54(s,1H),9.12(dt,J＝8.0,1.1Hz,1H),8.75–8.69(m,1H),8.67(dd,J＝7.5,1.5Hz,1H),8.51(s,1H),8.26–8.19(m,2H),8.02(td,J＝7.6,1.8Hz,1H),7.51(ddd,J＝7.5,4.7,1.2Hz,1H).HRESIMS m/z308.0603[M+H]+(calcd for C15H9N5OS 308.0606).
N-(5-硝基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：64％。1H NMR(600MHz,DMSO-d6)δ13.65(s,1H),9.10(dt,J＝8.0,1.1Hz,1H),8.78–8.73(m,2H),8.69(dd,J＝7.4,1.5Hz,1H),8.29–8.20(m,2H),8.10(td,J＝7.7,1.8Hz,1H),7.58(ddd,J＝7.5,4.8,1.2Hz,1H).13C NMR(151MHz,DMSO-D6)δ164.37,161.87,158.31,158.06,152.98,148.41,146.98,142.55,139.50,138.42,125.21,124.86,124.33,122.65.HRESIMS m/z 328.0500[M+H]+(calcd for C14H9N5O3S 328.0504).
N-(2'-氨基-[4,4'-联噻唑]-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：68％。1H NMR(600MHz,DMSO-d6)δ12.79(s,1H),9.17(dt,J＝8.0,1.1Hz,1H),8.72(ddd,J＝4.7,1.8,0.9Hz,1H),8.66(dd,J＝7.3,1.7Hz,1H),8.26–8.17(m,2H),8.05(td,J＝7.7,1.8Hz,1H),7.52(ddd,J＝7.5,4.7,1.3Hz,1H),7.32(s,1H),7.10(s,2H),6.93(s,1H),3.32(s,3H),3.16(d,J＝5.2Hz,3H).HRESIMS m/z381.0607[M+H]+(calcdfor C17H13N6OS2 381.0592).
N-(4-苯基噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：72％。1H NMR(600MHz,DMSO-d6)δ12.76(s,1H),9.09(dd,J＝8.0,1.2Hz,1H),8.80(d,J＝4.9Hz,1H),8.67(dd,J＝7.4,1.5Hz,1H),8.30–8.21(m,1H),8.12–8.05(m,1H),7.99–7.96(m,1H),7.95–7.90(m,1H),7.75(s,1H),7.68–7.58(m,1H),7.55–7.49(m,1H),7.46–7.38(m,2H),7.35–7.27(m,1H).13C NMR(151MHz,DMSO-D6)δ165.24,162.93,158.51,157.76,149.43,147.99,139.55,134.21,132.61,131.96,128.72,128.57,128.16,127.84,125.88,125.35,123.37,108.82.HRESIMS m/z359.0962[M+H]+(calcd forC20H14N4OS 359.0967).
N-(5-氨基-1,3,4-噻二唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：53％。1H NMR(600MHz,DMSO-d6)δ12.38(s,1H),9.09(dt,J＝7.9,1.1Hz,1H),8.71(ddd,J＝4.8,1.9,0.9Hz,1H),8.65(dd,J＝6.6,2.4Hz,1H),8.31–8.11(m,2H),8.02(td,J＝7.7,1.8Hz,1H),7.51(ddd,J＝7.4,4.7,1.2Hz,1H),6.97(s,2H).13C NMR(151MHz,DMSO-D6)δ165.02,162.08,154.94,153.99,149.09,148.69,147.82,139.15,137.30,124.77,123.96,123.30,122.19.HRESIMS m/z 299.0718[M+H]+(calcd forC13H10N6OS 299.0715).
N-(异噁唑-3-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：48％。1H NMR(600MHz,DMSO-d6)δ11.60(s,1H),9.07–8.95(m,1H),8.89(d,J＝1.8Hz,1H),8.78(d,J＝4.8Hz,1H),8.66(dd,J＝6.2,2.8Hz,1H),8.27–8.18(m,2H),8.15(t,J＝7.8Hz,1H),7.62(t,J＝6.3Hz,1H),7.11(d,J＝1.7Hz,1H).13CNMR(151MHz,DMSO-D6)δ162.87,160.46,157.41,148.59,148.05,139.54,139.24,125.37,124.35,123.59,122.66,116.44,114.51,99.84.HRESIMS m/z 267.0877[M+H]+(calcd forC14H10N6O2 267.0882).
N-(1,3,4-噻二唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：46％。1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),9.29(s,1H),9.13(dt,J＝8.0,1.1Hz,1H),8.76–8.74(m,1H),8.68(dd,J＝7.2,1.8Hz,1H),8.26–8.19(m,2H),8.12–8.07(m,1H),7.60–7.54(m,1H).13C NMR(151MHz,DMSO-D6)δ163.72,159.41,153.84,150.06,149.13,148.14,139.99,128.79,127.41,125.70,125.10,124.53,123.17.HRESIMS m/z 284.0602[M+H]+(calcd for C13H9N5O 284.0606).
N-(苯并噻唑-2-基)-[2,2'-联吡啶]-6-甲酰胺
白色固体，产率：52％。1H NMR(600MHz,DMSO-d6)δ9.13(dt,J＝8.0,1.1Hz,1H),8.88–8.84(m,1H),8.73(dd,J＝7.6,1.3Hz,1H),8.35–8.22(m,2H),8.17–8.12(m,1H),8.05(ddt,J＝35.5,7.9,1.0Hz,1H),7.87–7.74(m,1H),7.74–7.63(m,1H),7.60–7.54(m,1H),7.48(dddd,J＝24.9,8.3,7.1,1.3Hz,1H),7.36(dddd,J＝26.1,8.2,7.1,1.2Hz,1H).13CNMR(151MHz,DMSO-D6)δ163.99,158.93,158.68,158.42,149.16,148.33,140.27,133.44,132.30,129.20,128.87,126.89,126.74,124.55,124.25,122.45,122.30,121.25.HRESIMSm/z 333.0809[M+H]+(calcd for C18H12N4OS 333.0810).
N-(1H-吲哚-7-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：37％。1H NMR(600MHz,DMSO-d6)δ10.86(s,1H),8.98(d,J＝8.0Hz,1H),8.78(dd,J＝4.3,2.0Hz,1H),8.66(ddd,J＝6.0,3.1,1.1Hz,1H),8.30–8.20(m,2H),8.13(s,2H),7.65(d,J＝8.0Hz,1H),7.63–7.56(m,2H),7.14(t,J＝7.7Hz,1H).13C NMR(151MHz,DMSO-D6)δ163.17,158.96,158.71,150.14,148.85,148.78,142.98,142.93,139.91,127.89,127.50,126.72,125.79,124.19,123.69,122.87,120.94,118.54.HRESIMSm/z 316.1194[M+H]+(calcd for C18H13N5O 316.1198).
N-(1H-吲哚-3-基)-[2,2'-联吡啶]-6-甲酰胺
黄色固体，产率：27％。1H NMR(600MHz,DMSO-d6)δ12.91(s,1H),11.09(s,1H),9.01(dq,J＝8.0,1.3Hz,1H),8.75(d,J＝4.8Hz,1H),8.65(dd,J＝6.9,2.1Hz,1H),8.27–8.17(m,2H),8.06(t,J＝7.8Hz,1H),7.76(dd,J＝8.2,4.8Hz,1H),7.56(t,J＝6.2Hz,1H),7.49(d,J＝8.4Hz,1H),7.35(ddd,J＝8.3,6.8,1.1Hz,1H),7.08(dd,J＝8.1,6.9Hz,1H).13C NMR(151MHz,DMSO-D6)δ162.25,159.30,156.05,149.75,149.72,149.11,139.89,139.83,127.01,125.61,124.19,123.51,122.77,122.25,120.39,117.59,110.84.HRESIMS m/z316.1197[M+H]+(calcd for C18H13N5O 316.1198).
N-(4-氰基噻唑-2-基)-[2,4'-联吡啶]-6-甲酰胺
白色固体，产率：37％。1H NMR(600MHz,DMSO-d6)δ12.83(s,1H),8.87(dd,J＝5.0,0.8Hz,1H),8.81(dd,J＝2.0,0.8Hz,1H),8.77(ddd,J＝4.7,1.9,0.9Hz,1H),8.45(s,1H),8.36(dd,J＝5.1,1.8Hz,1H),8.24(dt,J＝8.0,1.1Hz,1H),7.99(td,J＝7.7,1.8Hz,1H),7.52(ddd,J＝7.6,4.7,1.1Hz,1H).13C NMR(151MHz,DMSO-D6)δ164.41,159.62,152.85,150.72,150.55,149.19,148.05,138.44,128.57,125.53,125.06,122.11,121.22,120.70,115.50.HRESIMS m/z 308.0605[M+H]+(calcd for C15H10N5OS 308.0606).
方案三，中间体的反应通式：
首先，使用schlenk高温高压管，化合物A(23.58mg，1mmol)溶于5mL甲苯中，向反应溶液中加入底物胺(1.05-1.4equiv)，无水碳酸钾106mg(1.4equiv)，三(二亚苄基丙酮)二钯3.6mg(4％mmol)，Xantphos 5.2mg(12％mmol)，氮气保护，110℃，反应20h。反应完成后，室温放凉，使用四氢呋喃稀释，并在减压下浓缩。将所得粗产物过柱，后通过硅胶柱，液相制备柱进行分离纯化，得到各实例化合物，产率17％-75％。
N-([2,2'-联吡啶]-6-基)噻唑-2-胺
黄色固体，产率：45％。1H NMR(600MHz,DMSO-d6)δ11.41(s,1H),8.66(ddd,J＝4.7,1.9,1.0Hz,1H),8.59(dt,J＝8.0,1.2Hz,1H),8.00(tt,J＝7.7,1.6Hz,1H),7.93(dt,J＝7.5,1.1Hz,1H),7.81(td,J＝7.7,1.3Hz,1H),7.43(ddd,J＝7.5,4.7,1.2Hz,1H),7.41(d,J＝3.6Hz,1H),7.09(d,J＝0.9Hz,1H),7.10–7.03(m,1H).13C NMR(151MHz,DMSO-D6)δ159.92,155.65,153.74,152.02,149.84,139.32,138.27,137.92,124.67,121.46,113.36,112.06,111.39.HRESIMS m/z 255.0706[M+H]+(calcd for C13H10N4S255.0704).
N-([2,2'-联吡啶]-6-基)-N-甲基噻唑-2-胺
白色固体，产率：33％。1H NMR(600MHz,DMSO-d6)δ8.69(ddd,J＝4.7,1.9,0.9Hz,1H),8.59(dt,J＝7.9,1.1Hz,1H),8.04(dd,J＝7.6,0.8Hz,1H),8.00(td,J＝7.7,1.9Hz,1H),7.97(dd,J＝8.4,7.5Hz,1H),7.48–7.42(m,2H),7.34(dd,J＝8.4,0.8Hz,1H),7.11(d,J＝3.6Hz,1H),3.81(s,3H).13C NMR(151MHz,METHANOL-D4)δ162.47,156.23,154.67,154.37,150.77,140.85,138.77,138.31,125.66,122.78,115.33,113.80,111.89,37.27.HRESIMS m/z 269.0858[M+H]+(calcd for C14H12N4S 269.0861).
2-([2,2'-联吡啶]-6-基氨基)噻唑-5-甲酸乙酯
白色固体，产率：33％。1H NMR(600MHz,DMSO-d6)δ12.04(s,1H),8.73–8.67(m,1H),8.52(d,J＝7.9Hz,1H),8.09(s,1H),8.05–7.97(m,2H),7.91(t,J＝7.9Hz,1H),7.47(ddd,J＝7.5,4.8,1.2Hz,1H),7.18(d,J＝8.1Hz,1H),4.25(d,J＝7.1Hz,2H),1.29(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-D6)δ161.74,156.09,154.76,153.31,149.49,145.74,139.34,137.25,133.48,128.81,124.39,120.80,118.81,114.23,60.48,14.19.HRESIMS m/z327.0913[M+H]+(calcd for C16H14N4O2S 327.0916).
2-([2,2'-联吡啶]-6-基氨基)噻唑-4-甲酰胺
黄色固体，产率：29％。1H NMR(600MHz,DMSO-d6)δ11.57(s,1H),8.70(ddd,J＝4.8,1.9,0.9Hz,1H),8.57(dt,J＝8.0,1.1Hz,1H),8.03(td,J＝7.7,1.8Hz,1H),7.99(dd,J＝7.5,0.9Hz,1H),7.91–7.83(m,1H),7.68(d,J＝0.8Hz,1H),7.57–7.53(m,1H),7.47(ddd,J＝7.5,4.7,1.2Hz,1H),7.24–7.21(m,1H),7.17(dd,J＝8.2,0.9Hz,1H).13CNMR(151MHz,DMSO-D6)δ162.77,158.83,154.87,153.19,151.30,149.30,144.88,138.96,137.38,124.15,120.87,115.16,113.27,111.66.HRESIMS m/z 298.0755[M+H]+(calcd forC14H11N5OS 298.0763).
N-(嘧啶-2-基)-[2,2'-联吡啶]-6-胺
黄色固体，产率：25％。1H NMR(600MHz,DMSO-d6)δ9.88(s,1H),8.66(ddd,J＝4.8,1.8,0.9Hz,1H),8.58(d,J＝4.8Hz,2H),8.41(dt,J＝7.9,1.2Hz,1H),8.34–8.27(m,1H),7.99(dd,J＝7.6,0.9Hz,1H),7.95(td,J＝7.7,1.8Hz,1H),7.90(t,J＝7.9Hz,1H),7.43(ddd,J＝7.5,4.7,1.3Hz,1H),6.98(t,J＝4.8Hz,1H).13C NMR(151MHz,DMSO-D6)δ159.75,158.73,155.66,154.12,153.00,149.70,139.36,137.67,124.61,121.14,114.52,114.24,113.62.HRESIMS m/z 250.1091[M+H]+(calcd for C14H11N5250.1093).
N-([2,3'-联吡啶]-6-基)噻唑-2-胺
黄色固体，产率：42％。1H NMR(600MHz,DMSO-d6)δ11.47(s,1H),9.44(dd,J＝2.3,0.9Hz,1H),8.67(dd,J＝4.8,1.6Hz,1H),8.58(ddd,J＝8.0,2.4,1.7Hz,1H),7.84(dd,J＝8.3,7.5Hz,1H),7.62(dd,J＝7.5,0.7Hz,1H),7.58(ddd,J＝7.9,4.7,0.9Hz,1H),7.45(d,J＝3.6Hz,1H),7.12(d,J＝3.6Hz,1H),7.10(dd,J＝8.2,0.7Hz,1H).13C NMR(151MHz,DMSO-D6)δ159.88,152.37,152.23,150.41,148.54,139.47,138.22,134.53,134.42,124.33,113.20,111.55,111.07.HRESIMS m/z 255.0707[M+H]+(calcd for C13H10N4S 255.0704).
N-([2,2'-联吡啶]-6-基)-1H-吲唑-3-胺
黄色固体，产率：31％。1H NMR(600MHz,DMSO-d6)δ8.80–8.75(m,1H),8.73(ddd,J＝4.8,1.9,0.9Hz,1H),8.43(dt,J＝7.9,1.1Hz,1H),8.10–8.04(m,2H),8.02–7.96(m,1H),7.93–7.87(m,2H),7.77(dd,J＝8.3,1.0Hz,1H),7.58(ddd,J＝8.3,7.0,1.2Hz,1H),7.49(dddd,J＝7.2,5.9,4.7,1.2Hz,2H),7.23(ddd,J＝7.9,6.9,0.9Hz,1H),6.24(s,2H).13CNMR(151MHz,DMSO-D6)δ156.58,155.13,153.60,151.59,149.44,140.84,139.15,137.61,128.50,124.52,120.95,120.71,120.46,119.76,118.50,114.39,111.78.HRESIMS m/z288.1244[M+H]+(calcd for C17H13N5 288.1249).
N-([2,2'-联吡啶]-6-基)-6-氟-1H-吲唑-3-胺
黄色固体，产率：22％。1H NMR(600MHz,DMSO-d6)δ8.74(ddd,J＝4.7,1.9,0.8Hz,1H),8.44(dd,J＝10.6,2.3Hz,1H),8.34(dt,J＝7.9,1.2Hz,1H),8.12–8.06(m,2H),8.03–7.99(m,1H),7.93(dd,J＝8.7,5.5Hz,1H),7.76(dd,J＝8.2,1.0Hz,1H),7.50(ddd,J＝7.5,4.7,1.2Hz,1H),7.12(td,J＝8.9,2.3Hz,1H),6.31(s,2H).13C NMR(151MHz,DMSO-D6)δ162.71,155.11,153.90,153.18,151.50,149.55,139.78,139.05,137.68,124.35,122.61,120.32,115.50,115.12,111.81,109.73,100.34.HRESIMS m/z 306.1149[M+H]+(calcdfor C17H12FN5 306.1155).
N-([2,2'-联吡啶]-6-基)-1,3,4-噻二唑-2-胺
黄色固体，产率：41％。1H NMR(600MHz,DMSO-d6)δ11.86(s,1H),9.07(s,0H),8.70(ddd,J＝4.7,1.8,0.8Hz,1H),8.52(dt,J＝7.9,1.1Hz,1H),8.06–8.00(m,2H),7.93–7.88(m,1H),7.48(ddd,J＝7.5,4.7,1.2Hz,1H),7.17(dd,J＝8.1,0.9Hz,1H).13C NMR(151MHz,DMSO-D6)δ159.64,154.77,153.32,150.61,149.36,146.36,139.35,137.40,124.23,120.84,113.71,111.88.HRESIMS m/z 256.0655[M+H]+(calcd for C12H9N5S256.0657).
N-([2,2'-联吡啶]-6-基)异恶唑-3-胺
白色固体，产率：43％。1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),8.69(d,J＝1.7Hz,1H),8.64(ddd,J＝4.7,1.9,0.9Hz,1H),8.26(dt,J＝8.0,1.1Hz,1H),7.93(td,J＝7.7,1.8Hz,1H),7.86(dd,J＝7.5,0.9Hz,1H),7.82–7.76(m,1H),7.44–7.37(m,1H),7.34(dd,J＝8.2,1.0Hz,1H),6.83(d,J＝1.8Hz,1H).13C NMR(151MHz,DMSO-D6)δ159.17,158.88,155.23,153.61,153.28,149.21,139.10,137.20,123.97,120.25,112.65,111.17,98.73.HRESIMS m/z 239.0932[M+H]+(calcd for C13H10N4O 239.0933).
N-([2,2'-联吡啶]-5-基)噻唑-2-胺
黄色固体，产率：38％。1H NMR(600MHz,Methanol-d4)δ10.64(s,1H),8.81(dd,J＝2.4,0.8Hz,1H),8.62(ddd,J＝4.8,1.9,0.9Hz,1H),8.35(qd,J＝8.7,1.7Hz,2H),8.29(dt,J＝8.0,1.1Hz,1H),7.88(td,J＝7.7,1.8Hz,1H),7.36(ddd,J＝7.4,4.7,1.3Hz,1H),7.33(d,J＝3.7Hz,1H),7.02(d,J＝3.6Hz,1H).13C NMR(151MHz,DMSO-D6)δ163.63,161.64,155.80,149.64,148.25,139.52,138.54,137.68,124.16,123.74,121.31,120.12,110.38.HRESIMS m/z 255.0702[M+H]+(calcd for C13H10N4S 255.0704).
2-([2,2'-联吡啶]-6-基氨基)-N-(4-(三氟甲氧基)苯基)噻唑-5-甲酰胺
黄色固体，产率：27％。1H NMR(600MHz,DMSO-d6)δ11.93(s,1H),10.31(s,1H),8.72(ddd,J＝4.7,1.8,0.8Hz,1H),8.58(dt,J＝7.9,1.1Hz,1H),8.34(s,1H),8.10–8.03(m,2H),7.96–7.90(m,1H),7.87–7.81(m,2H),7.52–7.46(m,1H),7.39–7.34(m,2H),7.19(dd,J＝8.1,0.9Hz,1H).13C NMR(151MHz,DMSO-D6)δ165.10,163.16,160.60,158.18,155.37,151.26,150.01,139.79,138.74,137.93,132.25,129.96,125.30,124.91,122.09,121.86,121.36,114.56,112.68.HRESIMS m/z 458.0897[M+H]+(calcd for C21H14F3N5O2S458.0899).
2-([2,2'-联吡啶]-6-基氨基)-N-(3,5-二氟苄基)噻唑-5-甲酰胺
白色固体，产率：35％。1H NMR(600MHz,DMSO-d6)δ11.80(s,1H),9.02(t,J＝6.0Hz,1H),8.71(ddd,J＝4.7,1.8,0.9Hz,1H),8.55(dt,J＝8.0,1.2Hz,1H),8.13(s,1H),8.05–7.99(m,2H),7.93–7.87(m,1H),7.48(ddd,J＝7.5,4.7,1.2Hz,1H),7.40(d,J＝3.6Hz,1H),7.20–7.16(m,1H),7.06–7.02(m,2H),4.47(d,J＝5.9Hz,2H).13C NMR(151MHz,DMSO-D6)δ163.14,161.97,161.43,154.82,153.31,150.80,149.38,144.59,140.29,139.11,137.31,129.00,128.81,128.52,126.18,124.25,120.77,113.76,110.18,110.01,41.74.HRESIMSm/z 424.1040[M+H]+(calcd for C21H15F2N5OS 424.1044).
2-([2,2'-联吡啶]-6-基氨基)-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)噻唑-5-甲酰胺
黄色固体，产率：17％。1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),10.56(s,1H),8.70(dt,J＝4.8,1.5Hz,1H),8.54(dt,J＝7.9,1.1Hz,1H),8.36(s,1H),8.23(s,1H),8.06(td,J＝7.7,1.8Hz,1H),8.04–8.02(m,2H),7.91(t,J＝7.8Hz,1H),7.69(s,1H),7.52(s,2H),7.47(ddd,J＝7.5,4.7,1.2Hz,1H),7.18(dd,J＝8.2,0.9Hz,1H),2.16(d,J＝1.1Hz,3H).13CNMR(151MHz,DMSO-D6)δ161.00,159.06,156.29,153.95,153.57,150.02,141.66,139.88,139.52,139.43,138.53,138.02,135.55,134.16,127.52,127.36,127.22,124.94,121.32,114.82,112.77,110.97,106.78,101.90,14.04.HRESIMS m/z 522.1323[M+H]+(calcd forC25H18F3N7OS 522.1324).
N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)-[2,2'-联吡啶]-6-胺
黄色固体，产率：56％。1H NMR(600MHz,DMSO-d6)δ10.09(d,J＝8.0Hz,1H),9.64–9.58(m,1H),8.70(dt,J＝4.5,1.5Hz,1H),8.58(q,J＝2.0Hz,1H),8.39(q,J＝2.0Hz,1H),8.26(dt,J＝8.0,1.1Hz,1H),8.07(q,J＝1.3Hz,1H),7.92(ddt,J＝7.7,6.1,1.9Hz,2H),7.85(t,J＝7.8Hz,1H),7.67(d,J＝1.8Hz,1H),7.47(ddd,J＝7.5,4.8,1.2Hz,1H),7.01(dd,J＝8.2,1.1Hz,1H),2.38(d,J＝1.0Hz,3H).13C NMR(151MHz,DMSO-D6)δ158.90,158.66,155.72,154.88,153.48,149.79,144.36,139.66,137.91,136.79,134.83,131.55,124.77,120.94,118.07,114.83,114.61,113.58,112.95,110.53,10.36.HRESIMS m/z396.1435[M+H]+(calcd for C21H16F3N5 396.1436).
2-([2,3'-联吡啶]-6-基氨基)-N-(2-氯-6-甲基苯基)噻唑-5-甲酰胺
白色固体，产率：37％。1H NMR(600MHz,Methanol-d4)δ11.88(s,1H),9.94(s,1H),9.40(dd,J＝2.4,0.9Hz,1H),8.65(dd,J＝4.8,1.6Hz,1H),8.52(dt,J＝8.1,2.0Hz,1H),8.31(s,1H),8.00–7.87(m,1H),7.67(d,J＝7.5Hz,1H),7.54(ddd,J＝8.0,4.7,0.9Hz,1H),7.40(dd,J＝7.9,1.7Hz,1H),7.33–7.22(m,2H),7.15(d,J＝8.2Hz,1H),2.24(s,3H).13CNMR(151MHz,DMSO-D6)δ160.52,152.50,151.66,150.56,148.52,141.62,139.92,139.38,134.63,134.25,134.01,132.99,129.58,128.77,127.54,124.96,124.36,114.43,111.61,18.83.HRESIMS m/z 422.0839[M+H]+(calcd for C21H15ClN5OS 422.0842).
2-([2,3'-联吡啶]-6-基氨基)-N-(4-(三氟甲氧基)苯基)噻唑-5-甲酰胺
黄色固体，产率：41％。1H NMR(600MHz,Methanol-d4)δ11.92(s,1H),10.29(s,1H),9.42(dd,J＝2.3,0.8Hz,1H),8.68(dd,J＝4.7,1.6Hz,1H),8.54(dt,J＝8.0,1.9Hz,1H),8.33(s,1H),7.94–7.88(m,1H),7.85–7.80(m,2H),7.68(d,J＝7.5Hz,1H),7.59(ddd,J＝8.0,4.7,0.9Hz,1H),7.15(d,J＝8.2Hz,1H).13C NMR(151MHz,DMSO-D6)δ163.15,160.59,152.52,151.62,150.60,148.56,144.23,141.90,139.95,138.72,134.62,134.25,132.12,131.89,128.68,125.51,124.38,122.09,121.84,114.51,111.65.HRESIMS m/z 458.0893[M+H]+(calcd for C21H14F3N5O2S 458.0899).
2-([2,2'-联吡啶]-5-基氨基)-N-(2-氯-6-甲基苯基)噻唑-5-甲酰胺
黄色固体，产率：39％。1H NMR(600MHz,Methanol-d4)δ11.16(s,1H),10.02(s,1H),9.13–8.78(m,1H),8.68(dt,J＝4.8,1.5Hz,1H),8.40(d,J＝21.0Hz,3H),8.21(s,1H),8.05(t,J＝7.7Hz,1H),7.50(t,J＝6.3Hz,1H),7.40(dd,J＝7.8,1.7Hz,1H),7.31–7.24(m,2H),2.23(s,3H).13C NMR(151MHz,DMSO-D6)δ166.35,158.61,148.30,142.67,140.94,139.89,139.29,139.12,138.58,137.13,133.76,132.87,129.64,128.91,127.59,125.58,124.66,122.19,121.20,18.77.HRESIMS m/z 422.0838[M+H]+(calcd for C21H15ClN5OS422.0842).
生物学活性
收集对数生长期细胞并以5×103细胞/孔的密度种于96孔板内，过夜培养后加药，以阿霉素，5-氟为阳性药，每个浓度设置3个副孔，继续培养72h。72h后取出96孔板，弃去培养基后每孔加入100μL 10％的三氯乙酸水溶液，4℃冰箱中固定至少2h。固定完成后取出96孔板，弃去三氯乙酸溶液，并用缓慢流动的水冲洗至少4遍并烘干，再加入80μL 1％醋酸配制的0.4％ SRB溶液染色20min，期间配置1％醋酸水溶液，染色结束后用1％醋酸水溶液冲洗4遍以去除未结合的染料，再次烘干。待96孔板完全干燥后每孔加入100μL 10mM Tris溶液，并震荡使与蛋白结合的染料完全溶解，置于酶标仪中于515nm处检测吸光度。
抑制率＝(对照组OD值-给药组OD值)/对照组OD值×100％，IC50值用Calcusyn软件计算得到。
表1活性化合物细胞毒的IC50(μM)
本发明具体实施方式公开了具体46个化合物及其化学合成方法，合成路线简单，易于操作和实施，并且所需试剂易于购买。同时测试了46个化合物对9种肿瘤细胞的增殖抑制活性，结果显示相比于此类天然产物的增殖抑制活性的30μM(IC50)，化合物的增殖抑制活性有了极大的提高，经过结构修饰之后活性可以达到几十至几百纳摩尔。另外，多个化合物的对多种癌细胞的增殖活性优于阿霉素的作用效果，与5-氟尿嘧啶结果相当，可以作为多种癌症相关疾病的治疗药物，也可作为蛋白抑制剂用于治疗相关疾病或病症的用途。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.联吡啶类化合物或其可药用的盐，其特征在于，所述联吡啶类化合物具有如下式I所示结构：
式I中：
X1、X2、X3分别独立为C原子或N原子且X1、X2、X3中有且仅有一个为N原子，Y1、Y2不相同且分别独立为C原子或N原子，L为酰胺键、酯键或N原子；
Ra、Rb分别独立为氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基或杂环基；
R1为烷基、烷氧基、环烷基或杂环基，其中烷基、烷氧基、杂环基可任选地被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、杂环基中的一个或多个取代基所取代。
2.联吡啶类化合物或其可药用的盐，其特征在于，所述联吡啶类化合物具有如下式II～XIV任一所示结构：
式II～XIV中，X1、X2、X3分别独立为C原子或N原子且X1、X2、X3中有且仅有一个为N原子，R2为H、羟基或烷氧基，R3为H或烷基；
式II、V、VIII、X、XII中，R4、R5分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基，或者，R4、R5连接成环；
式III中，R4、R5分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式IV、IX中，R5为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式VI、VII、XI中，R4-R8分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式XIII中，R4-R6分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基；
式XIV中，R4-R10分别独立为H、烷基、酰胺基、酯基、氰基、羟基烷基、硝基、芳香基、氨基、烷氧基、环烷基或杂环基。
3.根据权利要求2所述的联吡啶类化合物或其可药用的盐，其特征在于，所述联吡啶类化合物为以下任一化合物：
4.根据权利要求2所述的联吡啶类化合物的制备方法，其特征在于，所述联吡啶类化合物具有如式II～VII任一所示结构，所述制备方法为采用相应原料通过碱性条件下的酰胺化反应缩合形成酰胺键从而得到如式II～VII任一所示结构的联吡啶类化合物。
5.根据权利要求2所述的联吡啶类化合物的制备方法，其特征在于，所述联吡啶类化合物具有如式VIII～XIV任一所示结构，所述制备方法为采用相应原料通过连吡啶环或嗪环上的卤素原子与伯胺或叔胺在碱性条件、催化剂存在的情况下微波或加热进行偶联反应，从而得到如式VIII～XIV任一所示结构的联吡啶类化合物。
6.一种药物组合物，其特征在于，所述药物组合物含有根据权利要求1-3任一项所述的联吡啶类化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂和/或赋形剂。
7.根据权利要求1-3任一项所述的联吡啶类化合物或其可药用的盐，或者，根据权利要求6所述的药物组合物在制备用于治疗和/或预防疾病的药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述疾病为癌症。
9.根据权利要求8所述的应用，其特征在于，所述癌症为乳腺癌、子宫内膜癌、卵巢癌、阴道癌、输卵管癌、宫颈癌、肾癌、膀胱癌、尿路上皮癌、尿道癌、前列腺癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、鼻咽癌、口腔癌、肺癌、肺泡癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、神经纤维瘤、神经胶质瘤、神经母细胞瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌和胃肠道间质瘤。
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| CN115531387A (zh) * | 2016-10-26 | 2022-12-30 | 里格尔药品股份有限公司 | 用作irak抑制剂的吡唑酰胺化合物 |
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| US20180273510A1 (en) * | 2015-02-04 | 2018-09-27 | Beyondbio Inc. | Heterocyclic compound and pharmaceutical composition comprising same |
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